Abstract
Neuregulin, the putative ligand of the c-neu receptor tyrosine kinase, can induce differentiation or growth of epithelia and other cells. To gain insight into the biological role of this factor, we have analyzed the expression of neuregulin during mouse embryogenesis and in the perinatal animal by a combination of in situ hybridization and RNase protection experiments. We identify sites of expression that correspond to mesenchymal cells of various parenchymal organs. Our finding implies a function of neuregulin as a mesenchymal factor that acts on epithelia. The mesenchymal expression of neuregulin could thus provide a molecular basis for the biological phenomenon of mesenchymal-epithelial interactions. It also has implications on the molecular mechanism by which amplification of c-neu can affect tumor progression of carcinomas. In addition, neuregulin expression is found in neuronal cells during development. We show by RNase protection experiments that distinct isoforms of neuregulin are expressed in the brain. Therefore, our data indicate in vivo a dual role for neuregulin as mesenchymal and neuronal factor.
Full text
PDF![1064](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f6a/521454/77c0d758fcb0/pnas01125-0240.png)
![1065](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f6a/521454/baae1084d105/pnas01125-0241.png)
![1066](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f6a/521454/bc50bd7970c8/pnas01125-0242.png)
![1067](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f6a/521454/52d3c02fc510/pnas01125-0243.png)
![1068](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f6a/521454/7fe224727acb/pnas01125-0244.png)
Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bargmann C. I., Hung M. C., Weinberg R. A. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature. 1986 Jan 16;319(6050):226–230. doi: 10.1038/319226a0. [DOI] [PubMed] [Google Scholar]
- Birchmeier C., Birchmeier W. Molecular aspects of mesenchymal-epithelial interactions. Annu Rev Cell Biol. 1993;9:511–540. doi: 10.1146/annurev.cb.09.110193.002455. [DOI] [PubMed] [Google Scholar]
- Bladt F., Birchmeier C. Characterization and expression analysis of the murine rck gene: a protein kinase with a potential function in sensory cells. Differentiation. 1993 Jun;53(2):115–122. doi: 10.1111/j.1432-0436.1993.tb00651.x. [DOI] [PubMed] [Google Scholar]
- Coussens L., Yang-Feng T. L., Liao Y. C., Chen E., Gray A., McGrath J., Seeburg P. H., Libermann T. A., Schlessinger J., Francke U. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985 Dec 6;230(4730):1132–1139. doi: 10.1126/science.2999974. [DOI] [PubMed] [Google Scholar]
- Falls D. L., Rosen K. M., Corfas G., Lane W. S., Fischbach G. D. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell. 1993 Mar 12;72(5):801–815. doi: 10.1016/0092-8674(93)90407-h. [DOI] [PubMed] [Google Scholar]
- Goulding M. D., Lumsden A., Gruss P. Signals from the notochord and floor plate regulate the region-specific expression of two Pax genes in the developing spinal cord. Development. 1993 Mar;117(3):1001–1016. doi: 10.1242/dev.117.3.1001. [DOI] [PubMed] [Google Scholar]
- Holmes W. E., Sliwkowski M. X., Akita R. W., Henzel W. J., Lee J., Park J. W., Yansura D., Abadi N., Raab H., Lewis G. D. Identification of heregulin, a specific activator of p185erbB2. Science. 1992 May 22;256(5060):1205–1210. doi: 10.1126/science.256.5060.1205. [DOI] [PubMed] [Google Scholar]
- King C. R., Kraus M. H., Aaronson S. A. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science. 1985 Sep 6;229(4717):974–976. doi: 10.1126/science.2992089. [DOI] [PubMed] [Google Scholar]
- Orr-Urtreger A., Trakhtenbrot L., Ben-Levy R., Wen D., Rechavi G., Lonai P., Yarden Y. Neural expression and chromosomal mapping of Neu differentiation factor to 8p12-p21. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1867–1871. doi: 10.1073/pnas.90.5.1867. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peles E., Bacus S. S., Koski R. A., Lu H. S., Wen D., Ogden S. G., Levy R. B., Yarden Y. Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell. 1992 Apr 3;69(1):205–216. doi: 10.1016/0092-8674(92)90131-u. [DOI] [PubMed] [Google Scholar]
- Peles E., Ben-Levy R., Tzahar E., Liu N., Wen D., Yarden Y. Cell-type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/HER-2 suggests complex ligand-receptor relationships. EMBO J. 1993 Mar;12(3):961–971. doi: 10.1002/j.1460-2075.1993.tb05737.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Plowman G. D., Green J. M., Culouscou J. M., Carlton G. W., Rothwell V. M., Buckley S. Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Nature. 1993 Dec 2;366(6454):473–475. doi: 10.1038/366473a0. [DOI] [PubMed] [Google Scholar]
- Schechter A. L., Stern D. F., Vaidyanathan L., Decker S. J., Drebin J. A., Greene M. I., Weinberg R. A. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984 Dec 6;312(5994):513–516. doi: 10.1038/312513a0. [DOI] [PubMed] [Google Scholar]
- Slamon D. J., Godolphin W., Jones L. A., Holt J. A., Wong S. G., Keith D. E., Levin W. J., Stuart S. G., Udove J., Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
- Sonnenberg E., Gödecke A., Walter B., Bladt F., Birchmeier C. Transient and locally restricted expression of the ros1 protooncogene during mouse development. EMBO J. 1991 Dec;10(12):3693–3702. doi: 10.1002/j.1460-2075.1991.tb04937.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wen D., Peles E., Cupples R., Suggs S. V., Bacus S. S., Luo Y., Trail G., Hu S., Silbiger S. M., Levy R. B. Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell. 1992 May 1;69(3):559–572. doi: 10.1016/0092-8674(92)90456-m. [DOI] [PubMed] [Google Scholar]
- Yamamoto T., Ikawa S., Akiyama T., Semba K., Nomura N., Miyajima N., Saito T., Toyoshima K. Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature. 1986 Jan 16;319(6050):230–234. doi: 10.1038/319230a0. [DOI] [PubMed] [Google Scholar]